U.S. Patent 3,200,149 discloses the production of .alpha.-6-deoxytetracycline derivatives by a process which involves hydrogenation of certain 6-deoxy-6-demethyl-6-methylenetetracyclines in the presence of a catalytic amount of a noble metal catalyst such as rhodium or palladium. The process coproduces .beta.-6-deoxytetracyclines, as well as .alpha.-6-deoxytetracyclines. One of the major objectives of the present invention was to improve upon that process so as to produce a higher .alpha.-isomer to .beta.-isomer ratio.
It has now been found that a higher ratio of .alpha.-isomer to .beta.-isomer can be achieved by hydrogenating a mixture prepared from the .alpha.-deoxy-6-demethyl-6-methylenetetracycline compound and a specific, soluble rhodium(II) species, in a reaction-inert solvent. The specific soluble rhodium(II) species is a dicarboxylato(triphenylphosphine)rhodium(II) or dicarboxylato(substituted triphenylphosphine)rhodium(II) species.
West German Offenlegungsschrift 2,308,227 broadly discloses the use of soluble rhodium species for the stereoselective reduction of 6-deoxy-6-demethyl-6-methylenetetracyclines. However, the said Offenlegungsschrift exemplifies only the use of rhodium(I) species. Hui et al., Inorganic Chemistry, 12, 757 (1973), and Journal of the Chemical Society (London), Part D, 1195 (1970), report that rhodium(II) diacetate is an effective hydrogenation catalyst. However, use of rhodium(II) diacetate in the process of the present invention does not lead to a favorable .alpha. to .beta. ratio; approximately equal amounts of the .alpha.- and .beta.- isomers are formed. The presence of the triphenylphosphine or substituted triphenylphosphine ligand is essential to obtain a stereoselective reduction. Although Legzdins et al., Journal of the Chemical Society (London), Part D, 825 (1969) have reported the use of rhodium diacetate in the presence of triphenylphosphine as a hydrogenation catalyst, their experiments were run in the presence of a very strong acid. The process of the present invention is carried out under neutral conditions, or on a weakly-acidic tetracycline acid-addition salt.